ArticleProceedings of the National Academy of Sciences of the United States of America2011
Estrogen receptor α AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
50 citing papers in PubMed, 87 citations in OpenAlex.
- Estrogen-like potentiation of ghrelin-stimulated GH secretion by fulvestrant, a putatively selective ER antagonist, in postmenopausal women.The Journal of clinical endocrinology and metabolism · 2014Trial
- Subtle changes in ligand-receptor interactions dramatically alter transcriptional outcomes of pregnane X receptor modulators.Structure (London, England : 1993) · 2026Article
- Genome-wide association analysis highlights genomic regions and genes potentially associated with anestrus in crossbred gilts.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Differential Effects of Canonical Androgens and 11-Ketotestosterone on Reproductive Phenotypes and Folliculogenesis in Mouse Model of PCOS.Biomedicines · 2025Article
- Unraveling the Dynamics of Estrogen and Progesterone Signaling in the Endometrium: An Overview.Cells · 2024Review
- Nongenomic ERα-AMPK Signaling Regulates Sex-Dependent Bcrp Transport Activity at the Blood-Brain Barrier.Endocrinology · 2024Article
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Identification of a novel ESR1 mutation in a Chinese PCOS woman with estrogen insensitivity in IVF treatment.Reproductive biology and endocrinology : RB&E · 2022Article
- Endocrine and molecular factors of increased female reproductive performance in the Dummerstorf high-fertility mouse line FL1.Journal of molecular endocrinology · 2022Article
- Estrogen Receptor Function: Impact on the Human Endometrium.Frontiers in endocrinology · 2022Review
- The physiological role of estrogen receptor functional domains.Essays in biochemistry · 2021Review
- Estetrol and Mammary Gland: Friends or Foes?Journal of mammary gland biology and neoplasia · 2021Review
- Estrogen receptor-α signaling in post-natal mammary development and breast cancers.Cellular and molecular life sciences : CMLS · 2021Review
- 17β-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERα signaling.Molecular metabolism · 2020Article
- The genomic regulatory elements for estrogen receptor alpha transactivation-function-1 regulated genes.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Peri- and Postpubertal Estrogen Exposures of Female Mice Optimize Uterine Responses Later in Life.Endocrinology · 2020Article
- Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library.Molecules (Basel, Switzerland) · 2020Article
- ESR1 Mutations Associated With Estrogen Insensitivity Syndrome Change Conformation of Ligand-Receptor Complex and Altered Transcriptome Profile.Endocrinology · 2020Article
- The Impact of Estrogen Receptor in Arterial and Lymphatic Vascular Diseases.International journal of molecular sciences · 2020Review
- Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen-Responsive Cancer Cells via Activating Mutations.Journal of oncology · 2020Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
The estrogen receptor (ER) is a ligand-dependent transcription factor containing two transcriptional activation domains. AF-1 is in the N terminus of the receptor protein and AF-2 activity is dependent on helix 12 of the C-terminal ligand-binding domain. Two point mutations of leucines 543 and 544 to alanines (L543A, L544A) in helix 12 minimized estrogen-dependent transcriptional activation and reversed the activity of the estrogen antagonists ICI182780 (ICI) and tamoxifen (TAM) into agonists in a similar manner that TAM activated WT ERα through AF-1 activation. To evaluate the physiological role of AF-1 and AF-2 for the tissue-selective function of TAM, we generated an AF-2-mutated ERα knock-in (AF2ERKI) mouse model. AF2ERKI homozygote female mice have hypoplastic uterine tissue and rudimentary mammary glands similar to ERα-KO mice. Female mice were infertile as a result of anovulation from hemorrhagic cystic ovaries and elevated serum LH and E2 levels, although the mutant ERα protein is expressed in the AF2ERKI model. The AF2ERKI phenotype suggests that AF-1 is not activated independently, even with high serum E2 levels. ICI and TAM induced uterotropic and ER-mediated gene responses in ovariectomized AF2ERKI female mice in the same manner as in TAM- and E2-treated WT mice. In contrast, ICI and TAM did not act as agonists to regulate negative feedback of serum LH or stimulate pituitary prolactin gene expression in a different manner than TAM- or E2-treated WT mice. The functionality of the mutant ERα in the pituitary appears to be different from that in the uterus, indicating that ERα uses AF-1 differently in the uterus and the pituitary for TAM action.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.